The present invention is directed to methods of providing Oligomers which exhibit improved stability at acid pH, to methods of delivering such Oligomers to their sites of action and to their use in formulations for oral administration or other dosage forms where acid resistance is advantageous.
Depurination (loss of the purine bases from nucleosidyl units through cleavage of the glycosidic bond between the base and sugar) of deoxyribonucleic acid (DNA) under acidic conditions has been reported. (Hevesi, L., et al., J. Amer. Chem. Soc., 94, 4715-4720 (197). The oral delivery of therapeutic oligodeoxyribonucleotides may require exposure of the drug to the acidic conditions of the stomach (about pH 1) for up to about 4 hours under normal conditions of drug delivery and under conditions of sustained released drug delivery (see, e.g., U.S. Pat. No. 4,839,177), for up to about 12 hours. Due to its lack of stability under acid conditions, it is unlikely that enough of an orally administered oligodeoxynucleotide would remain intact to be effective. Ribonucleic acid (RNA) has been reported to be significantly more stable to depurination under acidic conditions than its DNA counterpart reportedly because of the apparent stabilizing effect of the 2' hydyoxyl on the glycosidic bond between sugar and the base (Hevesi, L., et al., supra).
Although RNA may be resistant to depurination under acid conditions, its sensitivity to ubiquitous nucleases present in biological materials limits its therapeutic usefulness. Furthermore, the use of oligoribonucleotides as a drug in its unmodified form is not feasible because of the inherent instability of the molecule to neutral to mildly basic conditions.
Unfortunately, protection of the RNA against nucleases by replacing the phosphate linkages with methylphosphonates is not possible because the 2'-hydroxyl of the sugar rapidly cleaves the methylphosphonate backbone.